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Pediatrics

Gestational diabetes and maternal obesity are associated with sex-specific changes in miRNA and target gene expression in the fetus

International Journal of Obesity volume 44, pages 1497–1507 (2020)Cite this article

Subjects

Abstract

Background/objectives

Pregnancies complicated by gestational diabetes (GDM) or maternal obesity have been linked to the development of diabetes, obesity, and fatty liver disease later in life with sex-specific manifestations. Alterations in miRNA expression in offspring exposed to GDM and maternal obesity and effects on hepatic development are unknown. Here, we describe how exposure to maternal obesity in utero leads to sex-specific changes in miRNA and target gene expression in human fetal liver.

Methods

Candidate miRNA expression was measured in second trimester amniotic fluid (AF) from women with GDM. Targets of differentially expressed miRNAs were determined and pathway enrichment of target genes was performed. MiRNA and target gene expression were measured in a separate cohort of second trimester primary human fetal hepatocytes (PHFH) exposed to maternal obesity via qPCR and western blot. All studies were IRB approved.

Results

GDM-exposed AF had significant increases in miRNAs 199a-3p, 503-5p, and 1268a (fold change (FC) ≥ 1.5, p < 0.05). Female offspring-specific analysis showed enrichment in miRNAs 378a-3p, 885-5p, and 7-1-3p (p < 0.05). MiRNA gene targets were enriched in hepatic pathways. Key genes regulating de novo lipogenesis were upregulated in obesity-exposed PHFH, especially in males. Significantly altered miRNAs in GDM AF were measured in obese-exposed PHFH, with consistent increases in miRNAs 885-5p, 199-3p, 503-5p, 1268a, and 7-1-3p (FC ≥ 1.5, p < 0.05). Female PHFH exposed to maternal obesity had increased expression of miR-885-5p, miR-199-3p, miR-503-5p, miR-1268s, and miR-7-1-3p (p < 0.05), corresponding to decreased target genes expression for ABCA1, PAK4, and INSR. In male PHFHs, no miRNA changes were measured but there was increased expression of ABCA1, PAK4, and INSR (p < 0.05).

Conclusions

Our data suggest sex-specific changes in miRNA and gene expression in PHFH may be one mechanism contributing to the sexual dimorphism of metabolic disease in offspring exposed to GDM and maternal obesity in utero.

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Acknowledgements

We would like to thank Jeanne Manson, Ph.D and Deborah Driscoll, M.D. for their work in establishing the amniotic fluid and amniocyte biospecimen repository.

Funding

Research reported in this publication was supported by the National Institute of Environmental Health Sciences and the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under award numbers SEP: K08 DK090302, P30 ES013508, UL1TR001878, the McCabe Foundation and the creation of the biospecimen repository: 5R21-ES11675.

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Authors and Affiliations

  1. Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Apoorva Joshi, Rikka Azuma, Rita Akumuo & Sara E. Pinney

  2. Department of Obstetrics, Gynecology and Reproductive Sciences, McGovern School of Medicine, University of Texas, Health Sciences Center at Houston, Houston, TX, USA

    Laura Goetzl

  3. Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

    Sara E. Pinney

  4. Center for Research in Reproduction and Women’s Health, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

    Sara E. Pinney

  5. Center of Excellence in Environmental Toxicology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

    Sara E. Pinney

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Correspondence to Sara E. Pinney.

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Joshi, A., Azuma, R., Akumuo, R. et al. Gestational diabetes and maternal obesity are associated with sex-specific changes in miRNA and target gene expression in the fetus. Int J Obes 44, 1497–1507 (2020). https://doi.org/10.1038/s41366-019-0485-y

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